Isoniazid mediates the CYP2B66 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6

Michael H Court; Fawziah E Almutairi; David J Greenblatt; Suwagmani Hazarika; Hongyan Sheng; Kathrin Klein; Ulrich M Zanger; Joanne Bourgea; Christopher J Patten; Awewura Kwara

doi:10.1128/AAC.02532-14

Back

Isoniazid mediates the CYP2B66 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6

Journal article

Open access

Peer reviewed

Isoniazid mediates the CYP2B66 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6

Michael H Court, Fawziah E Almutairi, David J Greenblatt, Suwagmani Hazarika, Hongyan Sheng, Kathrin Klein, Ulrich M Zanger, Joanne Bourgea, Christopher J Patten and Awewura Kwara

Antimicrobial agents and chemotherapy, Vol.58(7), pp.4145-4152

07/2014

DOI: https://doi.org/10.1128/AAC.02532-14

Handle:

https://hdl.handle.net/2376/114900

PMCID: PMC4068589

PMID: 24820076

Files and links (1)

url

https://doi.org/10.1128/AAC.02532-14View

Published (Version of record) Open

Abstract

Isoniazid - pharmacology

Cytochrome P-450 CYP2B6 - genetics

Ethambutol - pharmacology

Humans

Microsomes, Liver - metabolism

Antitubercular Agents - pharmacology

Benzoxazines - metabolism

Cyclopropanes

Cytochrome P-450 CYP2A6 - metabolism

Hydroxylation - drug effects

Enzyme Activation - drug effects

Cytochrome P-450 CYP2B6 - metabolism

Pyrazinamide - pharmacology

Drug Interactions

Benzoxazines - blood

Rifampin - pharmacology

Alkynes

Antitubercular Agents - therapeutic use

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [Ki] = 368 μM) and pyrazinamide (Ki = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [KI] = 30 μM; maximal rate constant of inactivation [kinact] = 0.023 min(-1)) and recombinant CYP2A6 (KI = 15 μM; kinact = 0.024 min(-1)) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.

Metrics

8 Record Views

Details

Title: Isoniazid mediates the CYP2B66 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6
Creators: Michael H Court - Individualized Medicine Program, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington, USA michael.court@vetmed.wsu.edu
Fawziah E Almutairi - Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, USA Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA
David J Greenblatt - Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, USA
Suwagmani Hazarika - Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, USA
Hongyan Sheng - Individualized Medicine Program, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington, USA
Kathrin Klein - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany
Ulrich M Zanger - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany
Joanne Bourgea - BD Biosciences, Discovery Labware, Woburn, Massachusetts, USA
Christopher J Patten - BD Biosciences, Discovery Labware, Woburn, Massachusetts, USA
Awewura Kwara - Warren Alpert Medical School of Brown University and The Miriam Hospital, Providence, Rhode Island, USA
Publication Details: Antimicrobial agents and chemotherapy, Vol.58(7), pp.4145-4152
Academic Unit: Plant Pathology, Department of; Veterinary Clinical Sciences, Department of
Publisher: United States
Grant note: R01 HD071779 / NICHD NIH HHS HHSN267200700004G / NLM NIH HHS R56 AI091448 / NIAID NIH HHS N01-DK-7-0004 / NIDDK NIH HHS HD-071779 / NICHD NIH HHS GM-061834 / NIGMS NIH HHS GM-102130 / NIGMS NIH HHS HHSN267200700004C / NIDDK NIH HHS R01 GM102130 / NIGMS NIH HHS R01 GM061834 / NIGMS NIH HHS AI-091448 / NIAID NIH HHS
Identifiers: 99900548194101842
Language: English
Resource Type: Journal article